[Eric Hofacket]

Targeting PARP14 to starve cancer cells of sugar

by Eric Hofacket on Mon Sep 28, 2015 1:58 pm

I know this is a hot and controversial topic of debate in the cancer community. I had not seen this article posted in the Beacon, so I thought I would post it.

It appears to researchers there is some merit to the idea of starving cancer cells of sugar to kill them. An idea that has been around for a long time. But it is not as simple as just cutting the intake of sugar in the diet. Not that most people would not seem some overall health benefit to cutting their sugar intake with diabetes and obesity being rampant.

In a recent study published in Nature Communications we showed that cancer cells stimulate the over-production of the protein known as PARP14, enabling them to use glucose to turbocharge their growth and override the natural check of cell death. Using a combination of genetic and molecular biology approaches, we have also demonstrated that inhibiting or reducing levels of PARP14 in cancer cells starves them to death."

From:

"How Starving Cancer Cells of Sugar Could Be the Best Way to Attack Them," Gizmodo, Sep 24, 2015 (full text of article)

Related journal article:

V Iansante et al., "PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation," Nature Communications, Aug 10, 2015 (full text of article)

[Edna]

Re: Targeting PARP14 to starve cancer cells of sugar

by Edna on Mon Sep 28, 2015 2:31 pm

Eric

The process by which the body gets the glucose needed to meet its extra energy demands is a process called gluconeogenesis by which proteins and fats can be converted to glucose through a series of biochemical steps. You do not really want body proteins broken down as there is no discrimination as to which part of the body the protein might come from e.g. heart.

The healthy view is not to see sugar as bad in itself, but to recognise the many foods e.g. fruits and vegetables, cereals, pulses provide it directly or through breakdown of carbohydrates. Whole grain cereals etc. are composed of complex carbohydrates and tend to release sugars more slowly. What is probably not needed is the added sugar in just about all foods these days.

In a test tube I suspect depriving cancer cells of glucose will stop their growth, unless something else can provide the glucose.

[withbellsMM]

Re: Targeting PARP14 to starve cancer cells of sugar

by withbellsMM on Mon Sep 28, 2015 3:58 pm

Hi Eric and Edna,

There is so much misunderstanding about sugar and cancer and I think it is because most people believe or were taught that the body can only use glucose (from carbs) or glutamate (from protein) for its fuel. There is also this huge panic that the brain needs glucose, and you will not last without it. So people (and even some nutritionists!) think that you will suffer somehow if you don't feed your body enough of the building blocks of glucose.

These arguments completely overlook the fact that the human body's default metabolism is to burn ketones (from fat) rather than glucose (from carbs). As babies, we are all born into ketosis and we burn fat from our mother's milk for energy. All the sugars in mother's milk are not for our energy, they are to feed the new bacteria in the gut and grow an immune system. It is perfectly safe to switch your metabolism from glucose-burning to fat-burning, though it could take from days to weeks (depending on how you are already eating) and could involve a fuzzy, lethargic transition period - followed by a great surge of energy once your new ketogenic metabolism kicks in.

Avoiding carbohydrates is one part of the puzzle, because these feed inflammation - and cancer cells selectively consume more glucose than regular cells (see: PET scan with radioactive glucose). But actually getting into ketosis is a more profound intervention because the ketones themselves are anti-inflammatory and work directly on cancer cells.

[Eric Hofacket]

Re: Targeting PARP14 to starve cancer cells of sugar

by Eric Hofacket on Mon Sep 28, 2015 4:00 pm

Edna,

The article said nothing about non-discriminatory breaking down of body proteins like heart tissue, or breaking down of any proteins. Is what you are referring is that cutting out all sugar and putting the body is a state where it uses just proteins and fat not necessarily a good thing?

I would agree and I am skeptical that this would actually do much to kill cancers cells. As you said, I feel there is way too much sugar in most western diets, so for most people reducing sugar, but not eliminating it completely, would benefit most people. I do not give a second thought about the sugars in raw fruits and vegetables, but I find it can be a real challenge when purchasing just about anything else to find products that do not have things like high fructose corn syrup added.

What I found interesting from the article is the discovery that one of the ways cancer cells change their metabolism from normal cells is to stimulate the overproduction of a protein known as PARP14 that enables cancer cells to use glucose to greatly increase their growth and “..override a natural check of cell death.” The researchers have demonstrated in vitro that inhibiting or reducing of levels of PARP14 in cells starves cancer cells to death.

What is also interesting is that looking at cancer tissues from patients that have survived cancer, compared to those that have died, found that PARP14 levels where significantly higher in those that have died, which is a good indication of the role PARP14 plays in cancer cells survival is not just an in vitro effect but it is in vivo as well.

The implication is that a drug that would inhibit the PARP14 protein could be selective in killing cancer cells, leaving normal cells healthy in a large number of cancers and mark a significant advancement in cancer treatments.

But I have to wonder if cancer cells, being the tricky beast they are, would not find a way to adapt around a PARP14 treatment like they have for so many other cancer treatments.

[Edna]

Re: Targeting PARP14 to starve cancer cells of sugar

by Edna on Mon Sep 28, 2015 4:24 pm

The article is not a scientific research paper, but one that speculates the role of sugar in the action of PARP14 in tumour tissue from the findings from some cancer patients. There is no mention of how many patients have been studied etc. So I do not want to read too much into it.

The body needs glucose as the 'immediate fuel' it uses for its activities, I was told the brain uses 20% of the glucose energy needs of the body. But what we do not need is the 'external' sugar put into food and drink whether by ourselves or the food manufacturers. If we have a healthy diet with plenty of fruits and vegetables and all other food groups we should be able to meet our glucose needs (unless we are sports persons or athletes), Glucose is very strictly controlled in the body (not in diabetes) and usually a little is stored in the liver wit the rest turned into fat.

Yes it is hard to find ready made foods without some variant of glucose in it. So cooking from scratch is the surest way to have 'sugar control'. But having said that there is no need to go to extremes to avoid sugar altogether in my view.

[Edna]

Re: Targeting PARP14 to starve cancer cells of sugar

by Edna on Mon Sep 28, 2015 4:44 pm

withbellsMM

Where is your scientific evidence for your assertion that

ketones themselves are anti-inflammatory and work directly on cancer cells.

Babies and Children under five differ from adults in that their rapid growth (including brain) requires the higher energy that fat provides (more than 2 times that of sugar) and they do not go into ketosis because of fat utilisation. Adults are not growing young children and can go into ketosis- hence the fuzzy brain etc. you note.

Added sugar in foods has no food value and is not needed, enough natural foods can provide the glucose we need as it is the adult body's default fuel, using fats and proteins when this is not available to meet energy needs.

If people want to go on a ketogenic diet that is up to them, but to believe it will cure them of cancer needs scientific evidence.

[Eric Hofacket]

Re: Targeting PARP14 to starve cancer cells of sugar

by Eric Hofacket on Mon Sep 28, 2015 5:04 pm

Edna,

The link to this article is from Gizmodo which is a web site I browse occasionally for tech and science news targeted at the general public. By no means is Gizmodo any kind of serious peer reviewed science journal and no serious researchers or any researchers I am aware of would publish their results in Gizmodo no more than a researcher would publish their findings of their research first in the Beacon. This articles purpose is to summarize and dumb down if you will for the general public researcher’s papers and finds from the more respected if you will peer reviewed journals such as Nature, The American Journal of Clinical Oncology, American Journal of Hematology etc , that most of us would never read and have difficulty understanding unless we were educated and worked in those fields. I do not believe this article is “speculating” on the role PARP14 plays in glucose and sugar or on anything but simply trying to summarize. The details of the researchers studies in this dumbed down summary are absent, important things like sample sizes and other statics etc, and to get those we would probably have to find the original published articles. I can see the possibility that in the process of summarizing and simplifying the original published findings there can be the possibility that important details can be miss-interrupted, subject to bias, or taken out of context, it happens. This is why I like it when the Beacons staff and medical advisers sometimes summarize the peer reviewed journal articles for us in terms and context that most us can understand at our level. Without the right level of education and knowledge it can be very difficult for most people to get that from reading the original published research papers who’s intended audience is the research peers and contemporaries working in that field, not the general public.

So to your point though, just on this Gizmado article by itself I feel we should be cautious about reading too much into it but I still feel this nothing here that suggest this is junk science, it is just not the whole story or anything about peer reviewed findings, duplication of results from other researchers etc.

[Edna]

Re: Targeting PARP14 to starve cancer cells of sugar

by Edna on Mon Sep 28, 2015 5:42 pm

Eric

I was not suggesting the article was junk science. I suppose I tend to look for more scientific data.. I take your point about making scientific findings accessible to non scientists.

Edna

[TerryS]

Re: Targeting PARP14 to starve cancer cells of sugar

by TerryS on Mon Sep 28, 2015 11:21 pm

Another theory on cancer cells use of sugar:

One of scientists’ great hopes in fighting cancer is the immune system. If the same cells that battle viruses and other invaders recognize a tumor as foreign, the expectation is that they should be able to attack the cancer.

Cancers, however, have many strategies for avoiding attacks from the immune system. But the more scientists are able to understand about those strategies, the more effectively they will be able to use the immune system to fight cancer.

To that end, researchers at Washington University School of Medicine in St. Louis have identified a new strategy. They found that if tumor cells take in enough glucose from their immediate environments, they effectively starve T cells — key immune system cells that defend the body — of this critical nutrient and render them unable to attack.

“This finding opens up a whole new aspect of the relationship between cancers and the immune system,” said senior author Erika Pearce, PhD, now at the Max Planck Institute of Immunobiology and Epigenetics in Germany. “If we can learn how to intercede, it could provide us with new ways to convince the immune system to fight cancer.” ...

Source:

"Cells’ lack of glucose dulls immune system’s ability to fight cancers," Washington University in St. Louis, Sep 24, 2015 (link to full text)

[Eric Hofacket]

Re: Targeting PARP14 to starve cancer cells of sugar

by Eric Hofacket on Tue Sep 29, 2015 8:17 am

Interesting finding Terry. My take away from that is while having lots of glucose is essential for cancer cells to thrive and survive, something that is widely accepted, they are not the only cells that need glucose to thrive and survive. Important cells like T cells that fight cancer need glucose too, and it appears that depriving local T cells of glucose is something that cancer cells do to render them unable to attack.

So does this mean that diets that result in extremely low glucose in the body might be coun­ter­productive because of the effects on T-cells?

The researchers in the article I posted the link to state that cancer cells, or maybe I should say the human body, have a means of adapting to extremely low glucose / carb diets so they are not really that effective at starving cancer cells, but there are those who would debate this.

Does this same mechanism adaptation apply to T-cells?

Even if it does, it may not matter much if what glucose does make it to the cancer cell area is used up by cancer cells locally, still starving the T-cells of glucose, but it may make an already low glucose environment for the T-cell even lower.

It appears the trick is to find a way to selectively starve the cancer cell of glucose inside the cancer cell itself while allowing other cells to have the glucose they need, and maybe a PARP14 inhibitor is the means to do so. I hope we hear these promising findings in the future.

Eric